More than 1/3 of Americans are overweight (obese), and it is important to identify new therapeutic treatments for this condition. A number of approached include liquid diets, calorie counting, fat counting, commercial weight loss programs, and the use of drugs. In the 1960's and 1970's amphetamines were the drug of choice, but they caused many problems including addiction. In the 1990's fenfluramine and phentemine are used to reduce the appetite. However, there are some major concerns about the use of thee drugs and the effects on serotonin centers. The objective of this proposal is to design, synthesize, characterize, and test tetrahydroisoquinline analogs for their ability to break down fat through he selective activation of betas-adrenoceptors. Dr. Miller will synthesize the designed molecules at The University of Tennessee. Dr. Purcell from MDI will work with us using the QSAR CoMFA program to optimize the structures for activation of beta3- adrenergic receptors and Dr. Feller, at The University of Mississippi, will test the compounds for the binding and activation of the three subtypes of human beta-adrenergic receptors. Selective beta3- adrenergic drugs will be useful for the treatment of obesity and non insulin dependent diabetes mellitus.